Bottom Line:
In contrast, two 5-hydroxytryptamine-3 (5-HT(3)) receptor antagonists, tropisetron and ondansetron, have been used to treat patients with chemotherapy-induced or postoperative nausea and vomiting.Furthermore, tropisetron, but not ondansetron, possesses high affinity for α7-nAChRs.Therefore, [(11)C]CHIBA-1001 may be a useful PET radioligand to measure the occupancy of α7-nAChRs in the human brain.

Objective: Agonists of α7-nicotinic acetylcholine receptors (nAChRs) have been developed as potential therapeutic drugs for neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. Positron emission tomography (PET) is a noninvasive brain imaging technique to measure receptor occupancy in the living human brain. Although much effort has been expended to create specific PET radioligands for α7-nAChRs in the brain, only 4-[(11)C]methylphenyl-1,4-diazabicyclo[3.2.2.]nonane-4-carboxylate ([(11)C]CHIBA-1001) is currently available for clinical studies. In contrast, two 5-hydroxytryptamine-3 (5-HT(3)) receptor antagonists, tropisetron and ondansetron, have been used to treat patients with chemotherapy-induced or postoperative nausea and vomiting. Furthermore, tropisetron, but not ondansetron, possesses high affinity for α7-nAChRs. In the present study, we evaluated the receptor occupancy in the human brain after a single oral administration of tropisetron and ondansetron using [(11)C]CHIBA-1001 and PET.

Methods: Two serial dynamic PET scans using [(11)C]CHIBA-1001 in healthy non-smoking male subjects were performed before and after receiving an oral administration of these medications.

Results: A single oral administration of tropisetron, but not ondansetron, decreased the total distribution volume of [(11)C]CHIBA-1001 in the human brain.

Conclusion: This study shows that tropisetron, but not ondansetron, could bind to α7-nAChRs in the human brain after a single oral administration. Therefore, [(11)C]CHIBA-1001 may be a useful PET radioligand to measure the occupancy of α7-nAChRs in the human brain.

Figure 2: Blocking rates of [11C]CHIBA-1001 by tropisetron and ondansetron. The mean±standard deviation of three subjects for each dose is shown.

Mentions:
Representative VT images of [11C]CHIBA-1001 before and after tropisetron (20 mg) and ondansetron (8 mg) loading are shown in Fig. 1. Radioactivity in the human brain after intravenous administration of [11C]CHIBA-1001 was widely distributed throughout, consistent with our previous report using postmortem human brain tissues.38) A single administration of 20 mg tropisetron decreased the VT of [11C] CHIBA-1001 in the brain (Fig. 1), whereas ondansetron (8 mg) had no effect. The mean blocking rates of the whole brain by 5 mg, 10 mg, and 20 mg tropisetron were 1.2±0.02% (mean±SD, n=3), 7.6±0.03% (n=3), and 14.1±0.02% (n=3), respectively. In contrast, the mean blocking rate of ondansetron of the whole brain was -0.4±0.03% (n=3). As shown in Fig. 2, single administration of tropisetron blocked the binding of [11C]CHIBA-1001 in the human brain in a dose-dependent manner, whereas a single administration of ondansetron had almost no effect. Furthermore, a significant (r=0.979, p<0.001) positive correlation was observed between the plasma concentration of tropisetron and the administered dose of tropisetron (Fig. 3).

Figure 2: Blocking rates of [11C]CHIBA-1001 by tropisetron and ondansetron. The mean±standard deviation of three subjects for each dose is shown.

Mentions:
Representative VT images of [11C]CHIBA-1001 before and after tropisetron (20 mg) and ondansetron (8 mg) loading are shown in Fig. 1. Radioactivity in the human brain after intravenous administration of [11C]CHIBA-1001 was widely distributed throughout, consistent with our previous report using postmortem human brain tissues.38) A single administration of 20 mg tropisetron decreased the VT of [11C] CHIBA-1001 in the brain (Fig. 1), whereas ondansetron (8 mg) had no effect. The mean blocking rates of the whole brain by 5 mg, 10 mg, and 20 mg tropisetron were 1.2±0.02% (mean±SD, n=3), 7.6±0.03% (n=3), and 14.1±0.02% (n=3), respectively. In contrast, the mean blocking rate of ondansetron of the whole brain was -0.4±0.03% (n=3). As shown in Fig. 2, single administration of tropisetron blocked the binding of [11C]CHIBA-1001 in the human brain in a dose-dependent manner, whereas a single administration of ondansetron had almost no effect. Furthermore, a significant (r=0.979, p<0.001) positive correlation was observed between the plasma concentration of tropisetron and the administered dose of tropisetron (Fig. 3).

Bottom Line:
In contrast, two 5-hydroxytryptamine-3 (5-HT(3)) receptor antagonists, tropisetron and ondansetron, have been used to treat patients with chemotherapy-induced or postoperative nausea and vomiting.Furthermore, tropisetron, but not ondansetron, possesses high affinity for α7-nAChRs.Therefore, [(11)C]CHIBA-1001 may be a useful PET radioligand to measure the occupancy of α7-nAChRs in the human brain.

Objective: Agonists of α7-nicotinic acetylcholine receptors (nAChRs) have been developed as potential therapeutic drugs for neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. Positron emission tomography (PET) is a noninvasive brain imaging technique to measure receptor occupancy in the living human brain. Although much effort has been expended to create specific PET radioligands for α7-nAChRs in the brain, only 4-[(11)C]methylphenyl-1,4-diazabicyclo[3.2.2.]nonane-4-carboxylate ([(11)C]CHIBA-1001) is currently available for clinical studies. In contrast, two 5-hydroxytryptamine-3 (5-HT(3)) receptor antagonists, tropisetron and ondansetron, have been used to treat patients with chemotherapy-induced or postoperative nausea and vomiting. Furthermore, tropisetron, but not ondansetron, possesses high affinity for α7-nAChRs. In the present study, we evaluated the receptor occupancy in the human brain after a single oral administration of tropisetron and ondansetron using [(11)C]CHIBA-1001 and PET.

Methods: Two serial dynamic PET scans using [(11)C]CHIBA-1001 in healthy non-smoking male subjects were performed before and after receiving an oral administration of these medications.

Results: A single oral administration of tropisetron, but not ondansetron, decreased the total distribution volume of [(11)C]CHIBA-1001 in the human brain.

Conclusion: This study shows that tropisetron, but not ondansetron, could bind to α7-nAChRs in the human brain after a single oral administration. Therefore, [(11)C]CHIBA-1001 may be a useful PET radioligand to measure the occupancy of α7-nAChRs in the human brain.